Regulation of LOXL2 and SERPINH1 by antitumor microRNA-29a in lung cancer with idiopathic pulmonary fibrosis
Regulation of LOXL2 and SERPINH1 by antitumor microRNA-29a in lung cancer with idiopathic pulmonary fibrosis
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DOI：
10.1038/jhg.2016.99
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发表时间：
2016-12-01
影响因子：
3.5
通讯作者：
Inoue, Hiromasa
中科院分区：
文献类型：
--
作者：
Kamikawaji, Kazuto;Seki, Naohiko;Inoue, Hiromasa
特发性肺纤维化（IPF）是一种慢性进行性肺疾病，难以治疗，死亡率高。IPF常与肺癌相关。鉴定两种疾病中涉及的分子靶点可能阐明有助于其病理的新分子机制。最近对microRNA （miRNA）表达特征的研究表明，microRNA-29a （miR-29a）在IPF和肺癌中下调。本研究旨在探讨miR-29a在肺癌细胞（A549和EBC-1）和肺成纤维细胞（MRC-5）中的功能意义，并确定miR-29a在这些细胞中调节的分子靶点。我们在IPF和肺癌的临床标本中证实了miR-29a的下调。miR-29a的恢复抑制癌细胞的侵袭性和成纤维细胞的迁移。基因表达数据和计算机分析的结合表明，总共有24个基因是miR-29a的假定靶点。其中，赖氨酸氧化酶样2 （LOXL2）和丝氨酸肽酶抑制剂分支H，成员1 （SERPINH1）是通过荧光素酶报告基因检测miR-29a的直接靶点。LOXL2和SERPINH1的功能对胶原的生物合成有重要作用。LOXL2和SERPINH1在肺癌和纤维化病变的临床标本中均有过表达。miR-29a下调导致LOXL2和SERPINH1在肺癌和IPF中过表达，提示这些基因参与了这两种疾病的发病机制。
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease that is refractory to treatment and carries a high mortality rate. IPF is frequently associated with lung cancer. Identification of molecular targets involved in both diseases may elucidate novel molecular mechanisms contributing to their pathology. Recent studies of microRNA (miRNA) expression signatures showed that microRNA-29a (miR-29a) was downregulated in IPF and lung cancer. The aim of this study was to investigate the functional significance of miR-29a in lung cancer cells (A549 and EBC-1) and lung fibroblasts (MRC-5) and to identify molecular targets modulated by miR-29a in these cells. We confirmed the downregulation of miR-29a in clinical specimens of IPF and lung cancer. Restoration of miR-29a suppressed cancer cell aggressiveness and fibroblast migration. A combination of gene expression data and in silico analysis showed that a total of 24 genes were putative targets of miR-29a. Among them, lysyl oxidase-like 2 (LOXL2) and serpin peptidase inhibitor clade H, member 1 (SERPINH1) were direct targets of miR-29a by luciferase reporter assays. The functions of LOXL2 and SERPINH1 contribute significantly to collagen biosynthesis. Overexpression of LOXL2 and SERPINH1 was observed in clinical specimens of lung cancer and fibrotic lesions. Downregulation of miR-29a caused overexpression of LOXL2 and SERPINH1 in lung cancer and IPF, suggesting that these genes are involved in the pathogenesis of these two diseases.